Abstract
BACKGROUND: Fraktaline, otherwise known as CX3CL1, is a chemokine that can act on microglia to promote the release of matrix metalloproteinases (MMPs). Additionally, CX3CL1 can upregulate MMP‐9 which has been associated with alterations in memory and vasculature remodeling. MMP‐9 has also been shown to interact with tau protein, as well as APP processing, and its levels are higher in APOE4 carriers. Therefore, we examined the role of MMP‐9 in the CX3CL1‐CX3CR1 pathway in APOE4 carriers (APOE+) compared to noncarriers (APOE‐), as well as its implication on tau and amyloid pathology. METHODS: Cerebrospinal fluid samples were collected from 116 cognitively unimpaired veterans, aged 50‐76, participating in the Brain Amyloid and Vascular Effects of Eicosapentaenoic acid (BRAVE) study (NCT02719327). We designed a custom electrochemiluminescent assay to quantify MMP‐9 levels using the Meso Scale Discovery SQ120. A NULISAseq CNS Disease Panel was used to quantify CX3CL1, ptau217, Aβ40, Aβ42 and the Roche Cobas Analyzer measured total tau. RESULTS: In APOE‐ individuals, CX3CL1 had a direct effect on ptau217 levels (B = 0.77, SE = 0.17, p < .001, 95% CI [0.42, 1.11], with a standardized effect of β=0.44) with no mediating role of MMP‐9 (β = –0.0006, BootSE = 0.01, 95% CI [–0.025, 0.021]). CX3CL1 positively correlated with ptau217 (p <.001), Aβ40 (p <.001) and Aβ42 (p <.001). We found a negative correlation between CX3CL1 and ptau217/total tau (p <.001), as well as ptau217/Aβ42 (p =.013). MMP‐9 did not correlate with Aβ40, Aβ42, Aβ42/Aβ40, ptau217, ptau217/total tau, or ptau217/Aβ42 (p >0.05). However, in APOE+ carriers, MMP‐9 played a significant mediating role in the pathway involving CX3CL1 on ptau217 (β = 0.46, 95% CI [0.10, 0.75]). Importantly, MMP‐9 had a positive correlation between ptau217 (p <.001), CX3CL1 (p <.001), Aβ40 (p <.001) and a negative relationship with Aβ42/Aβ40 (p =.013) and ptau217/total tau (p <.001). CONCLUSION: We propose that APOE+ carriers experience a dysregulated CX3CL1 signaling pathway that is mediated by MMP‐9 with implications on tau regulation. Specifically, MMP‐9 is recruited into the CX3CL1 signaling pathway to reduce ptau217 phosphorylation in APOE+ carriers. If replicated, targeting MMP‐9 could be beneficial in therapeutic interventions focusing on the reduction of ptau217 pathology in neurodegenerative disorders in those who are APOE+.